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Abstract: SA-OR112

Sirtuin 3 Mediates Sex Differences in Ischemia-Reperfusion Kidney Injury

Session Information

Category: Women’s Health and Kidney Diseases

  • 2000 Women’s Health and Kidney Diseases

Authors

  • Pan, Jenny S., Baylor College of Medicine, Houston, Texas, United States
  • Shen, Huiyun, Baylor College of Medicine, Houston, Texas, United States
  • Li, Qingtian, Baylor College of Medicine, Houston, Texas, United States
  • Sheikh-Hamad, David, Baylor College of Medicine, Houston, Texas, United States
Background

Biologic sex influences susceptibiity to AKI, a common condition with limited therapies. Mitochondrial dysfunction and oxidative stress play key roles in the pathogenesis of ischemic AKI. Our observations reveal higher baseline kidney expression of mitochondrial SIRT3 (mtSIRT3), a major mitochondrial deacetylase, in female vs male mice. We hypothesize that SIRT3 confers protection and mediates sex differences in response to kidney ischemia-reperfusion injury (IRI).

Methods

Male and female wild-type (WT), SIRT3 transgenic (Tg), or inducible kidney tubule-specific SIRT3 knockout (KO) mice were subjected to bilateral kidney IRI (clamping of renal pedicles for 30 min). HEK cells were treated with 17β-estradiol (E2), testosterone or veh.

Results

We observe higher mtSIRT3 expression in kidneys of WT female vs. male mice; mtSIRT3 declines with age but sex differences persist. At age 6-months, SIRT3 Tg male mice display less tubular vacuolization and ROS vs similarly aged WT males. Male Tg mice demonstrate resistance to IRI [preserved creatinine clearance (CrCl) and morphology; less ROS] and better survival vs WT males; outcomes similar to WT females. In contrast at age 6-months, SIRT3 KO males display greater tubular injury vs WT males. SIRT3 KO mice demonstrate increased susceptibility to IRI [decreased CrCl; worse morphological changes; increased ROS] and worse survival vs WT. In WT females, kidney mtSIRT3 correlates positively with plasma E2 and negatively with testosterone (T) levels. In WT males, kidney mtSIRT3 only correlates negatively with plasma T. In HEK cells, E2 treatment increases SIRT3 mRNA, and whole cell- and mtSIRT3 protein; T decreases mtSIRT3 protein with no effect on whole cell SIRT3 or SIRT3 mRNA. We previously showed that LRP2 shuttles intracrine proteins to the mitochondria and physically associates with SIRT3. Current observations show higher baseline kidney expression of LRP2 in WT female vs male. Testosterone treatment decreases LRP2 protein expression. In vitro LRP2 knockdown decreases mtSIRT3 protein.

Conclusion

1) SIRT3 ameliorates kidney IRI, and decreased SIRT3 in males mediates the increased susceptibility to ischemic injury; 2) sex steroids regulate mtSIRT3 expression; estrogen via transcriptional regulation and testosterone via inhibition of LRP2-mediated mitochondrial targeting; 3) sex differences in AKI pathophysiology need to be studied.

Funding

  • Veterans Affairs Support